Sibutramine on Cardiovascular Outcome

S ibutramine, a combined norepinephrine and serotonin reuptake inhibitor, is effective in the management of obese patients requiring pharmacotherapy as part of a multimodal approach to weight loss. It improves insulin resistance markers, glucose metabolism, and atherogenic dyslipidemia in both diabetic and nondiabetic patients, most of these effects resulting fromweight loss. However, sibutramine exerts a peripheral sympathomimetic effect that induces a moderate increase in heart rate and attenuates the reduction in blood pressure attributable to weight loss or even slightly increases blood pressure. Since 2002, several cardiovascular adverse events (hypertension, tachycardia, arrhythmias, myocardial infarction) were reported in sibutramine-treated patients. This led to a contraindication of the use of this antiobesity agent in patients with established coronary heart disease, previous stroke, heart failure, or cardiac arrhythmias. The recent Sibutramine Cardiovascular Outcomes Trial (SCOUT) confirmed that subjects with preexisting cardiovascular disease (CVD) on long-term (5 years) treatment with sibutramine (10–15 mg/day) had a significantly increased risk for nonfatal myocardial infarction and nonfatal stroke, but not cardiovascular death or all-cause mortality. Because the benefit of sibutramine as a weight loss aid seems not to outweigh the cardiovascular risks, the European Medicines Agency (EMEA) recommended the suspension of marketing authorizations for sibutramine across the European Union (EU). The U.S. Food and Drug Administration (FDA) first stated that the drug should carry a “black box”warning because of an increased risk of stroke and heart attack in patients with a history of CVD. In October 2010, however, sibutramine was withdrawn from the U.S. market. After SCOUT, concern still persists about the effect of sibutramine on cardiovascular outcome. Obesity is a major cause of morbidity and mortality, predominantly through CVDs (1,2). The metabolic consequences of obesity, more particularly abdominal obesity associated with increased visceral adipose tissue, include atherogenic dyslipidemia, impaired glucose metabolism, hypertension, and silent inflammation, all CVD risk factors (3,4). Weight loss is considered to be the initial step that helps to prevent or to control the clinical consequences of obesity (5,6), especially in patients with type 2 diabetes (7). However, the current state of weight reduction in the prevention and treatment of CVD remains controversial (5,8). No longterm, large-scale study of intentional weight loss by medical means has been adequately powered to examine CVD end points in obese individuals with or without diabetes. The initial clinical strategy for weight loss is lifestyle modification involving a combination of diet, exercise, and behavior change (1,2). Pharmacological therapy can be offered to obese patients who fail to achieve their weight loss goals through diet and exercise alone (9,10). It should be considered for those with BMI .30 kg/m or BMI .27 kg/m with obesity-related risk factors or disease. Although.5% of placebo-subtracted weight loss maintained over 1 year is the primary efficacy end point, an associated reduction in CVD risk factors is considered as an important secondary end point that may help for grant approval by the FDA and the EMEA (11). Safety aspects are also critical in this indication essentially because antiobesity compounds may be associated with adverse events, and several of them have been withdrawn from the market because of toxicity (12). Sibutramine is one of the few established and well-proven agents for obesity and should be considered effective in the management of patients requiring pharmacotherapy as part of a multimodal approach to weight loss (13–16). The pharmacological mechanisms by which sibutramine exerts its weight loss effect are likely because of a combination of reduced appetite, feelings of satiety, and possibly the induction of thermogenesis (Fig. 1). Its efficacy for inducing an initial weight reduction and the subsequent maintenance of the weight loss is well proven in shortand long-term clinical trials of up to 2-years duration (17,18). Sibutramine was also shown to improve insulin resistancemarkers and atherogenic dyslipidemia, part of this effect possibly occurring beyond weight loss (19–21). Several randomized clinical trials were performed in overweight/obese patients with type 2 diabetes demonstrating the potential of sibutramine to improve blood glucose control and other CVD risk factors in this population (22,23). However, its action on the sympathetic nervous system has linked sibutramine to blood pressure and heart rate elevations (24,25). This raised the possibility of increased CVD risk despite the favorable weight-reducing effect of the drug (26). For that reason, sibutramine’s use is contraindicated in patients with uncontrolled hypertension, coronary heart disease, cardiac dysrhythmias, congestive heart failure, or stroke (27,28). This review article discusses the perceived CVD risks of sibutramine and focuses on cardiovascular outcomes in overweight/obese patients with or without type 2 diabetes.